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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
  • C07D239/52—Two oxygen atoms
  • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
  • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
  • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
  • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D473/00—Heterocyclic compounds containing purine ring systems
  • C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• European patent application No. 0,079,083 describes, inter alia, the compound of the formula ##STR2## which has positive inotropic properties. It has now been found that novel 2-phenyl-imidazoles of the formula ##STR3## and the tautomers and acid addition salts thereof, particularly the pharmacologically acceptable acid addition salts thereof with inorganic or organic acids, which differ from the known 2-phenylimidazole derivatives either in their substituent R 1 or in the groups A, B, C, and D, have superior pharmacological properties, particularly an effect on the contractility of the cardiac muscle.
• A, B, C, and D each represent a nitrogen atom optionally substituted by a hydrogen atom or by an alkyl group having from 1 to 3 carbon atoms; a carbon atom substituted by a hydrogen atom, a halogen atom, a hydroxyl group, a benzyloxy group, or an alkoxy group having from 1 to 3 carbon atoms; or a carbonyl group, with the proviso that at least one of the groups A, B, C, and D represents a nitrogen atom optionally substituted by a hydrogen atom or an alkyl group and another of the groups A, B, C, and D represents a carbon atom substituted by a halogen atom or by a hydroxyl, benzyloxy, or alkoxy group, or a carbonyl group;
• R 1 represents a nitrilo, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonyl, or alkanoylamino group, where each alkyl, alkoxy, or alkanoyl moiety has from 1 to 3 carbon atoms, or
• R 1 may also represent an aminosulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl group, where each alkyl moiety may have from 1 to 3 carbon atoms, or
• R 1 may also represent an alkylmercapto, alkylsulfinyl, or alkylsulfonyl group having from 1 to 3 carbon atoms in each alkyl moiety, or
• A represents a nitrogen atom optionally substituted by a hydrogen atom or by an alkyl group and the phenyl group is substituted in the 2-position by an alkoxy or dialkylamino group
• it may also represent a halogen atom or an alkyl, nitro, carboxyl, amino, alkylamino, dialkylamino, or benzyloxy group or an alkoxy group in the 5-position or else, if the groups A, B, C, and D together with the imidazole ring do not represent a theophylline group, it may also represent an alkoxy group in the 4-position, where each alkyl or alkoxy moiety may contain from 1 to 3 carbon atoms, or
• A represents a nitrogen atom substituted by a hydrogen atom or by an alkyl group and R 2 and R 3 do not represent hydrogen atoms, it may also represent a halogen atom or a nitro, benzyloxy, hydroxysulfonyl, or alkoxy group, where each alkyl or alkoxy moiety has from 1 to 3 carbon atoms, or
• R 1 may also represent a halogen atom or an alkyl, hydroxyl, benzyloxy, alkoxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, hydroxysulfonyl, nitro, amino, alkylamino, or dialkylamino group, where each alkyl or alkoxy moiety may have from 1 to 3 carbon atoms, or
• R 1 may also represent a halogen atom or an alkyl, hydroxyl, benzyloxy, alkoxy, alkylmercapto, alkysulfinyl, alkylsulfonyl, hydroxysulfonyl, nitro, amino, alkylamino, or dialkylamino group, where each alkyl or alkoxy moiety may have from 1 to 3 carbon atoms, or
• R 1 may also represent a benzyloxy, alkylmercapto, alkylsulfinyl, or alkylsulfonyl group or, if the groups A, B, C, and D together with the imidazole ring do not represent a xanthine group, R 1 may also represent an alkyl, hydroxyl, alkoxy, nitro, amino, alkylamino, or dialkylamino group, where each alkyl or alkoxy moiety may have from 1 to 3 carbon atoms, or
• R 1 may also represent a halogen atom or an alkyl, nitro, amino, alkylamino, dialkylamino, hydroxyl, alkoxy, hydroxysulfonyl, or carboxyl group, where each alkyl or alkoxy moiety may have from 1 to 3 carbon atoms;
• R 2 and R 3 which may be the same or different, each represent a hydrogen atom, a halogen atom, or an alkyl, hydroxyl, alkoxy, benzyloxy, alkylmercapto, alkylsulfinyl, alkylsulfonyl, nitro, amino, alkylamino, dialkylamino, alkanoylamino, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, nitrilo, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl group, where each alkyl, alkoxy, or alkanoyl moiety may have from 1 to 3 carbon atoms.
• the present invention thus relates to the novel 2-phenylimidazo[4,5-d]pyridazin-4-ones, 2-phenyl-imidazo[4,5-b]pyridines, 2-phenyl-imidazo[4,5-b]-pyridin-5-ones, 6-hydroxy-2-phenylimidazo[4,5-c]pyridin-4-ones, 2-phenyl-imidazo[4,5-c]pyridin-4-ones, 2-phenyl-imidazo[4,5-c]pyridin-6-ones, 2-phenyl-imidazo[4,5-d]pyridazin-4,7-dione, 2-phenyl-imidazo[4,5-d]pyridazine, 2-phenyl-imidazo[4,5-c]pyridazin-6-one, 2-phenyl-imidazo[4,5-c]pyridazine, 8-phenyl-xanthine, 8-phenyl-purin-2-one, 8-phenylpurin-6
• R 1 to R 3 the hydrogen, fluorine, chlorine, and bromine atoms and the hydroxysulfinyl, aminosulfonyl, methylaminosulfonyl, ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, di-n-propylaminosulfonyl, methyl-ethylaminosulfonyl, ethyl-isopropylaminosulfonyl, nitrilo, aminocarbonyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, di-n-isopropylaminocarbonyl,
• Preferred compounds of Formula I above are those wherein
• A, B, C, and D each represent a nitrogen atom optionally substituted by a hydrogen atom or a methyl group; a carbon atom substituted by a hydrogen, chlorine, or bromine atom or by a hydroxyl, methoxy, or benzyloxy group; or a carbonyl group, but at least one of the groups A, B, C, and D should represent a nitrogen atom substituted by a chlorine atom or by a hydroxyl, methoxy, or benzyloxy group, or a carbonyl group;
• R 1 represents a nitrilo, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methoxycarbonyl, or acetylamino group, or
• R 1 may also represent an aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl group, or
• R 1 may also represent a methylmercapto, methylsulfinyl, or methylsulfonyl group of, if A represents a nitrogen atom optionally substituted by a hydrogen atom or by a methyl group and the phenyl ring is substituted in the 2-position by a methoxy, ethoxy, propoxy, or dimethylamino group, R 1 may also represent a chlorine or bromine atom or a methyl, nitro, amino, methylamino, dimethylamino, or benzyloxy group or a methoxy group in the 5-position or, if the groups A, B, C, and D together with the imidazole ring do not represent a theophylline group, R 1 may also represent a methoxy group in the 4-position, or
• R 1 may also represent a chlorine or bromine atom or a nitro, hydroxysulfonyl, methoxy, ethoxy, propoxy, or benzyloxy group, or
• R 1 may also represent a chlorine atom or a methyl, hydroxyl, benzyloxy, methoxy, ethoxy, propoxy, methylmercapto, methylsulfinyl, methylsulfonyl, hydroxysulfonyl, amino, methylamino, or dimethylamino group, or
• R 1 may also represent a chlorine atom or a methyl, hydroxyl, methoxy, ethoxy, propoxy, benzyloxy, methylmercapto, methylsulfinyl, methylsulfonyl, hydroxysulfonyl, nitro, amino, methylamino, or dimethylamino group, or
• R 1 may also represent a methylmercapto, methylsulfinyl, or methylsulfonyl group or, if the groups A, B, C, and D together with the imidazole ring do not represent an xanthine group, R 1 may also represent a methyl, hydroxyl, methoxy, ethoxy, propoxy, nitro, amino, methylamino, or dimethylamino group, or
• R 1 may also represent a chlorine or bromine atom or a methyl, nitro, amino, methylamino, dimethylamino, hydroxyl, methoxy, ethoxy, propoxy, benzyloxy, methylmercapto, methylsulfinyl, methylsulfonyl, hydroxysulfonyl, or carboxyl group;
• R 2 represents a hydrogen, chlorine, or bromine atom or a methyl, hydroxyl, methoxy, ethoxy, benzyloxy, methylmercapto, methylsulfinyl, methylsulfonyl, nitro, amino, methylamino, dimethylamino, acetylamino, aminosulfonyl, methylaminosulfonyl, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, or dimethylaminocarbonyl group; and
• R 3 represents a hydrogen atom or a dimethylamino, hydroxyl, methoxy, ethoxy, or propoxy group.
• R 1 in the 4- or 5-position is as hereinbefore defined;
• R 3 in the 3-position is as hereinbefore defined with the proviso that R 3 does not represent a hydrogen atom;
• R 2 represents a hydrogen, chlorine, or bromine atom or a nitro, aminosulfonyl, or methylaminosulfonyl group.
• R 1 in the 4-position represents a benzyloxy, methylmercapto, methylsulfinyl, methylsulfonyl, aminosulfonyl, methylaminosulfonyl, or dimethylaminosulfonyl group;
• R 3 in the 2-position represents a methoxy group
• R 2 represents a hydrogen atom
• the new compounds are obtained by the following methods:
• Z 1 and Z 2 which may be identical or different, represent optionally substituted amino groups or hydroxyl or mercapto groups optionally substituted by lower alkyl groups, or
• Z 1 and Z 2 together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having from 1 to 3 carbon atoms, or an alkylenedioxy or alkylenedithio group having 2 to 3 carbon atoms,
• the cyclization is advantageously carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin, or pyridine or in an excess of the acylating agent used to prepare the compound of Formula II, e.g., in the corresponding nitrile, anhydride, acid halide, ester, amide, or methoiodide, for example, at temperatures of from about 0° to 250° C., preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfuryl chloride, sulfuric acid, p-toluenesulfonic acid, hydrochloric acid, phosphoric acid,
• the oxidation is preferably carried out in a solvent or mixture of solvents, e.g., in water, water/pyridine, aceton, glacial acetic acid, dilute sulfuric acid, or trifluoroacetic acid, advantageously at temperatures of from about -80° to 100° C., dependent upon the oxidizing agent used.
• a solvent or mixture of solvents e.g., in water, water/pyridine, aceton, glacial acetic acid, dilute sulfuric acid, or trifluoroacetic acid, advantageously at temperatures of from about -80° to 100° C., dependent upon the oxidizing agent used.
• oxidation is advantageously carried out with one equivalent of the oxidizing agent used, e.g., with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid, or formic acid at brom about 0° to 20° C. or in acetone at from about 0° to 60° C., with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at from about 0° to 50° C. or with m-chloroperbenzoic acid in methylene chloride or chloroform at from about -20° C.
• the oxidizing agent e.g., with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid, or formic acid at brom about 0° to 20° C. or in acetone at from about 0° to 60° C.
• a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at from about 0° to 50° C. or with
• oxidation is advantageously carried out with one or with two or more equivalents of the oxidizing agent used, e.g., with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid, or formic acid at from about 20° to 100° C.
• acetone at from about 0° to 60° C.
• a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures of from about 0° to 60° C., with nitric acid in glacial acetic acid at 0° to 20° C., or with chromic acid or potassium permanganate in glacial acetic acid, water/sulfuric acid, or acetone at from about 0° to 20° C.
• V represents a hydroxyl group or an amino group optionally substituted by one or two alkyl groups, each having from 1 to 3 carbon atoms.
• the reaction is advantageously carried out in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, methylene chloride, ether, tetrahydrofuran, dioxane, dimethylformamide, or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate triethylamine, or pyridine, while these latter two may simultaneously be used as solvent as well, preferably at temperatures of from about 0° to 100° C., e.g., at temperatures of between ambient temperature and 50° C.
• solvents such as water, methanol, ethanol, isopropanol, methylene chloride, ether, tetrahydrofuran, dioxane, dimethylformamide, or benzene
• an acid-binding agent such as sodium carbonate triethylamine, or pyridine
• the reaction is advantageously carried out in a solvent or mixture of solvents such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g., in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, or triphenylphosphine/carbon tetrachloride, or an agent activating the amino group, e.g., phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or
• any water formed during the reaction may be removed by azeotropic distillation, e.g., by heating with toluene using a water separator or by adding a drying agent such as magnesium sulfate or molecular sieve.
• R 6 represents a hydroxyl, alkoxy, or phenylalkoxy group, where the alkyl moiety may have from 1 to 3 carbon atoms.
• the reaction is advantageously carried out either in the presence of an acid such as hydrochloric, sulfuric, phosphoric, or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide or the alkali metal salt of a corresponding alcohol, in the melt or in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, or water/dioxane at temperatures of from about -10° to 120° C., e.g., at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
• an acid such as hydrochloric, sulfuric, phosphoric, or trichloroacetic acid
• a base such as sodium hydroxide or potassium hydroxide or the alkali metal salt of a corresponding alcohol
• a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol, or water/dioxane at temperatures of from about -10° to 120
• any ether groups present may simultaneously be converted into hydroxyl groups.
• reaction is optionally carried out in a solvent such as benzene in the presence of an acylating agent such as acetic anhydride or propionic anhydride, the latter conveniently being used as solvent as well, at elevated temperatures, preferably at the boiling temperature of the solvent used.
• a solvent such as benzene
• an acylating agent such as acetic anhydride or propionic anhydride, the latter conveniently being used as solvent as well, at elevated temperatures, preferably at the boiling temperature of the solvent used.
• the optional subsequent hydrolysis is conveniently carried out in water, water/methanol, water/dioxane, or methanol in the presence of an acid such as hydrochloric acid or a base such as sodium hydroxide solution or ammonia, at the boiling temperature of the reaction mixture.
• an acid such as hydrochloric acid or a base such as sodium hydroxide solution or ammonia
• the hydrogenolysis is conveniently carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, ethyl acetate, dimethylformamide, or water, optionally in the presence of an inorganic acid such as hydrochloric or hydrobromic acid at temperatures of from about -10° C. to 100° C., preferably at from about 0° to 60° C., in the presence of a catalyst such as platinum, platinum oxide, or palladium on charcoal.
• a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, ethyl acetate, dimethylformamide, or water
• an inorganic acid such as hydrochloric or hydrobromic acid
• a catalyst such as platinum, platinum oxide, or palladium on charcoal.
• the hydrazinolysis is advantageously carried out with hydrazine or hydrazine hydrate in a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, or ethylene glycol dimethyl ether or without a solvent at temperatures of between 0° C. and the boiling temperature of the reaction mixture.
• a solvent such as water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, or ethylene glycol dimethyl ether
• a compound of Formula I wherein at least one of the groups A, B, C, and D represents an alkoxymethine group and/or at least one of the groups R 1 , R 2 , and R 3 represents a cyano group, it may be converted by hydrolysis and/or alcoholysis into a corresponding compound of Formula I wherein at least one of the groups A, B, C, and D represents a carbonyl or hydroxymethine group and/or at least one of the groups R 1 , R 2 , and R 3 represents an aminocarbonyl or alkoxycarbonyl group, and/or
• a compound of Formula I wherein at least one of the groups R 1 , R 2 , and R 3 represents a nitro group may be converted by reduction into a corresponding compound of Formula I in which at least one of the groups R 1 , R 2 , and R 3 represents an amino group, and/or
• a compound of Formula I wherein at least one of the groups R 1 , R 2 , and R 3 represents an amino group may be converted by alkanolyation into a corresponding compound of Formula I in which at least one of the groups R 1 , R 2 , and R 3 represents an alkanoylamino group, and/or
• a compound of Formula I wherein at least one of the groups R 1 , R 2 , and R 3 represents an amino group may be converted via its diazonium salt into a corresponding compound of Formula I in which at least one of the groups R 1 , R 2 , and R 3 represents a halogen atom or a hydroxy or cyano group, and/or
• a compound of Formula I wherein at least one of the groups R 1 , R 2 , and R 3 represents an aminocarbonyl group may be converted by dehydration into a corresponding compound of Formula I in which R 1 represents a cyano group.
• the subsequent hydrolysis and/or alcoholysis is carried out in the presence of an inorganic base with hydrogen peroxide, e.g., with 2N sodium hydroxide solution or potassium hydroxide solution/hydrogen peroxide, in the melt with an inorganic base, e.g., in a potassium hydroxide melt, in the presence of an acid or in the presence of an alcoholic hydrohalic acid at temperatures of from about 0° to 50° C., preferably at ambient temperature.
• an inorganic base with hydrogen peroxide e.g., with 2N sodium hydroxide solution or potassium hydroxide solution/hydrogen peroxide
• an inorganic base e.g., in a potassium hydroxide melt
• an acid or in the presence of an alcoholic hydrohalic acid at temperatures of from about 0° to 50° C., preferably at ambient temperature.
• the subsequent reduction of the nitro compound is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate, or dimethylformamide, advantageously with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum, or palladium/charcoal, with metals such as iron, tin, or zinc in the presence of an acid, with salts such as iron(II) sulfate, tin(II) chloride, or sodium dithionate, or with hydrazine in the presence of Raney nickel, at temperatures of from about 0° to 50° C., preferably at ambient temperature.
• a hydrogenation catalyst such as Raney nickel, platinum, or palladium/charcoal
• metals such as iron, tin, or zinc
• an acid with salts such as iron(II) sulfate, tin(II) chloride, or sodium dithionate, or with hydrazine in the presence of
• the subsequent acylation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, or dimethylformamide, preferably with a reactive derivative of the alkanoic acid, for example, with the acid chloride or the anhydride, optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously serve as solvent, at temperatures of from about -25° to 250° C., preferably at temperatures between -10° C. and the boiling temperature of the solvent used.
• a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, or dimethylformamide
• a diazonium salt e.g., the fluoroborate
• the fluoride in 40% hydrofluoric acid
• the hydrosulfate in sulfuric acid or the hydrochloride
• copper or a corresponding copper(I) salt such as copper(I) chloride/hydrochloric acid or copper(I) bromide/hydrobromic acid
• slightly elevated temperatures e.g., at temperatures of from about 15° to 100° C.
• the diazonium salt required is appropriately prepared in a suitable solvent, e.g., in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid, or dioxane/hydrochloric acid, by diazotizing a corresponding amino compound with a nitrite, e.g., sodium nitrite or an ester of nitrous acid, at low temperatures, e.g., at temperatures of from about -10° to 5° C.
• a suitable solvent e.g., in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid, or dioxane/hydrochloric acid
• the subsequent dehydration is carried out with a dehydrating agent such as phosphorus pentoxide, sulfuric acid, or p-toluenesulfonic acid chloride, optionally in a solvent such as methylene chloride, or pyridine at temperatures of from about 0° to 100° C., preferably at temperatures of from about 20° to 80° C.
• a dehydrating agent such as phosphorus pentoxide, sulfuric acid, or p-toluenesulfonic acid chloride
• a solvent such as methylene chloride, or pyridine
• the compounds of Formula I obtained may, if desired, be converted into their pharmacologically acceptable acid addition salts with inorganic or organic acids.
• Suitable acids include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric, succinic, tartaric, citric, lactic, maleic, and methanesulfonic acid.
• the compounds of Formula II used as starting materials are obtained by acylating a corresponding o-diamino compound, and the compounds of Formulae III, IV, VI, VII, and X to XII are obtained by subsequent condensation with a corresponding benzoic acid derivative and optionally subsequent oxidation (see, European patent application No. 0,022,495).
• novel compounds of Formula I, the 1H tautomers thereof, and the pharmacologically acceptable acid addition salts thereof have superior pharmacological properties, particularly in terms of their duration of activity, a positive inotropic activity and/or an effect on blood pressure.
• the compounds of Formula I, the 1H tautomers thereof, and the pharmacologically acceptable acid addition salts thereof have superior pharmacological properties, particularly in terms of their duration of activity, a positive inotropic activity and/or an effect on blood pressure.
• the tests were carried out on cats anaesthetised with sodium pentobarbital (40 mg/kg i.p.). The animals breathed spontaneously. The arterial blood pressure was measured in the aorta abdominalis with a Statham pressure transducer (P 23 Dc). To determine the positive inotropic activity, the pressure in the left ventricle was measured with a catheter-tip manometer (Millar PC-350 A). From this the contractility parameter dp/dt max was determined using an analogue differentiator. The test substances were injected into a vena fermoralis. The solvent used was physiological saline solution or Polydiol 200. Each substance was tested on at least 3 cats, dosage 2 mg/kg i.v.
• the new compounds are well tolerated, and no toxic effects on the heart or damage to the circulation of any kind could be detected in the tests on compounds A to C.
• the compounds of Formula I according to the invention and the pharmacologically acceptable acid addition salts thereof are suitable for the treatment of cardiac insufficiency of various origins since they increase the contractile force of the heart and partly by lowering blood pressure they facilitate the emptying of the heart.
• novel compounds of Formula I and the pharmacologically acceptable acid addition salts thereof optionally in combination with other active ingredients, preferably substances which additionally guard against infection by microbes, such as sulfonamides, or antibiotics, e.g., tetracycline, doxycycline, ampicillin, amoxycillin, cephalexin, or erythromycin, may be administered to warm-blooded hosts perorally, parenterally, or rectally as active ingredients in customary preparation forms suitable for the intended purposes, that is, compositions consisting essentially of one or more inert conventional carriers and/or diluents, e.g., corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene, glycol, propylene glycol, carboxymethylcellulose, or fatty substances such
• the active ingredient or a mixture of different active ingredients may be administered orally to both humans or animals, in a single dose of from about 23 to 165 mg (0.3 to 2.2 mg/kg of body weight), preferably from about 50 to 113 mg (0.7 to 1.5 mg/kg of body weight), 1 to 4 times a day.
• a daily dose is therefore from about 23 to 660 mg (from about 0.3 to 8.8 mg/kg of body weight), preferably from about 113 to 450 mg (from about 0.7 to 6.0 mg/kg of body weight).
• the optimum dosage and route of administration of active ingredient necessary in each case can easily be determined by one skilled in the art.
• a quantity of 0.07 gm of 2-(2-methoxy-4-methylsulfinyl-phenyl)-5H-imidazo[4,5-d]pyridazin-4-one is dissolved in 5 ml of glacial acetic acid, mixed with 0.05 ml of 30% hydrogen peroxide, and stirred first for 55 minutes at ambient temperature then for two hours at 40°-50° C., Then, a further 0.05 ml of hydrogen peroxide are added, and the mixture is heated for another hour. The product precipitated is subjected to suction filtration and washed with ether.
• a suspension of 1.4 gm of 3-[(2-dimethylamino-4-nitro-benzoyl)-amino]-2-amino-6-methoxy-pyridine in 40 ml of phosphorus oxychloride is refluxed for three hours.
• the phosphorus oxychloride is evaporated off by about two-thirds, and the residue is poured into water.
• the solution obtained is made ammoniacal, and the product precipitated is purified over a silica gel column [eluant: methylene chloride/ethanol (100:0 to 100:0.5)].
• a quantity of 0.2 gm of 2-(2-dimethylamino-4-nitro-phenyl)-5-methoxy-imidazo[4,5-b]pyridine is heated in a bomb tube to 100° C. for three hours with 5 ml of concentrated hydrochloric acid.
• the reaction mixture is poured onto about 20 ml of ice, neutralized, and extracted with ethyl acetate. After washing with water and drying with magnesium sulfate, the ethyl acetate phase is evaporated. The residue is crystallized by trituration in ether/petroleum ether.
• a quantity of 1.36 gm of 2-(2,4-dimethoxy-phenyl)-4H-imidazo[4,5-b]pyridin-5-one is added to 5 ml of chlorosulfonic acid at 0° C., and the mixture is stirred at 20°-30° C. for 24 hours. It is poured onto ice, and the precipitate formed is filtered off. This is added in batches to 100 ml of concentrated ammonia and stirred overnight at ambient temperature. The precipitate remaining is filtered off, and the filtrate is adjusted to a pH of 5 to 6 with glacial acetic acid. The precipitate formed is centrifuged off and digested with water. The precipitate remaining is filtered off and stirred with acetone.
• Amounts of 8.51 gm of 4,5-diamino-1,3-dimethyl-uracil and 9.91 gm of 2-methoxy-4-methylmercapto-benzoic acid are refluxed for 5.5 hours together with 200 ml of phosphorus oxychloride. Then, any excess phosphorus oxychloride is evaporated off, and the residue is decomposed with ice water. The precipitate obtained is recrystallized from ethanol.
• a quantity of 3.7 gm of 8-(2-methoxy-4-methylmercapto-phenyl)-1,3-dimethyl-1H,3H-purin-2,6-dione is suspended in 30 ml of 50% acetic acid, and 1.8 gm of anhydrous sodium acetate are added thereto. Then, 1.6 gm of bromine (dissolved in 1.5 ml of glacial acetic acid) are added dropwise to the mixture, with stirring. The resulting mixture is stirred for a further 20 minutes, poured onto ice, and made ammoniacal, and the precipitate is recrystallized from ethanol.
• a quantity of 0.6 gm of 8-(4-amino-2-dimethylamino-phenyl)purin-6-one is heated to 150° C. in 5 ml of acetic anhydride for one hour. The mixture is evaporated to dryness in vacuo and recrystallized from acetone/ether.
• a quantity of 0.6 gm of 2-(2-dimethylamino-4-amino-phenyl)imidazo[4,5-b]pyridin-5-one is refluxed with 20 ml of acetic anhydride for 30 minutes. After evaporation, 10 ml of concentrated ammnoia and then 20 ml of ice are added. The product precipitated is suction filtered and washed with water.
• a quantity of 1.27 gm of 5,6-diamino-2H-1,2,4-triazin-3-one is refluxed for thirty minutes in 50 ml of pyridine with stirring. Then, 4.33 gm of 2-methoxy-4-methylmercapto-benzoyl chloride are added, and the mixture is refluxed for a further two hours.
• the percipitate is suction filtered while hot and washed with water.
• the solid product obtained is stirred in 2N sodium hydroxide solution for 15 minutes at ambient temperature. The solid product remaining is filtered off, the filtrate is neutralized with glacial acetic aicd, and the precipitate obtained is extracted by boiling with water.
• the compound is obtained from the mixture described in Example 54 as the second fraction in the column separation.
• a quantity of 2.3 gm of 8-(2-methoxy-4-carboxy-phenyl)-1H,-3H-purin-2,6-dione are refluxed for one hour in 50 ml of thionyl chloride with the addition of 1 drop of dimethylformamide.
• the excess thionyl chloride is drawn off, and the residue is stirred for 16 hours at ambient temperature with a solution of ammonia in dimethylformamide.
• the dimethylformamide is drawn off, the remainder is mixed with water and acidified with glacial acetic acid, and the product precipitated is filtered off.
• Example 40 Prepared analogously to Example 40 from 2-methoxy-8-(2-benzyloxy-5-methoxy-phenyl)-purine. The compound crystallizes as the hydrate.
• Example 2 Prepared analogously to Example 1 from 2-methoxy-3,4-diaminopyridine and 2-methoxy-4-cyano-benzoic acid.
• the product mixture obtained is digested with dichloroethane/ethanol (3:1).
• the undissolved material is filtered off, and the solution is evaporated and boiled with methanolic hydrochloric acid. On cooling, the product crystallizes out in the form of the hydrate.
• Example 103 Prepared as in Example 103.
• the insoluble product obtained is purified over silica gel [eluant: dichloroethane/ethanol (100:0 to 95:5)].
• compositions comprising a compound of the present invention as an active ingredient and represent the best modes contemplated of using the invention.
• the compound 8-(2-methoxy-4-methylmercaptophenyl)-purin-2-one has been used as the active substance.
• one or more other compounds of Formula I or tautomers or pharmacologically acceptable acid addition salts thereof can be used as active substance in place of said compound.
• Each tablet has the following composition:
• the active substance and lactose are homogeneously moistened with an aqueous solution of polyvinyl pyrrolidone, passed through a screen with a mesh size of 1.5 mm, dried in a circulating air drier at 50° C., and passed through a screen with a mesh size of 1 mm. After addition of the carboxymethylcellulose and magnesium stearate, the resulting mixture is compressed to form tablets:
• Each tablet core has the following composition:
• the active substance and starch are moistened homogeneously with an aqueous solution of the soluble starch, passed through a screen of mesh size of 1 mm, dried at 50° C. in a circulating air drier, and again passed through a 1 mm mesh screen. After addition of the carboxymethylcellulose and magnesium stearate, the mixture is pressed to form tablet cores.
• the finished cores are given a sugar coating in a coating pan in the conventional manner.
• Weight of coated tablet 120 mg
• Each suppository has the following composition:
• the suppository mass is melted, and after the molten mass has been cooled to 38° C., ground active substance is homogeneously dispersed therein. The molten mass is then cooled to 35° C. and poured into slightly chilled suppository molds.
• Each ampule contains the following:
• the active substance and sorbitol are dissolved in distilled water and then made up to the given volume, and the resulting solution is filtered under sterile conditions.
• One hundred milliliters of drop solution has the following composition:
• the benzoates are dissolved in ethanol, and then the anisole and menthol are added.
• the active substance, glycerol, and sodium saccharin, all dissolved in water, are then added.
• the solution is then filtered clear.

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• 1983
  • 1983-12-28 DE DE19833347290 patent/DE3347290A1/de not_active Withdrawn
• 1984
  • 1984-11-27 ES ES537992A patent/ES8601992A1/es not_active Expired
  • 1984-12-19 DK DK610284A patent/DK610284A/da unknown
  • 1984-12-20 EP EP84116009A patent/EP0149200A1/de not_active Withdrawn
  • 1984-12-20 US US06/684,052 patent/US4722929A/en not_active Expired - Fee Related
  • 1984-12-25 JP JP59281991A patent/JPS60172980A/ja active Pending
  • 1984-12-27 PT PT79755A patent/PT79755B/pt unknown
  • 1984-12-27 GR GR82597A patent/GR82597B/el unknown
  • 1984-12-27 DD DD84271864A patent/DD231355A5/de unknown
  • 1984-12-27 FI FI845117A patent/FI845117L/fi not_active Application Discontinuation
  • 1984-12-27 IL IL73951A patent/IL73951A0/xx unknown
  • 1984-12-27 KR KR1019840008436A patent/KR850004476A/ko not_active Application Discontinuation
  • 1984-12-27 HU HU844843A patent/HUT37618A/hu unknown
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  • 1984-12-28 AU AU37211/84A patent/AU3721184A/en not_active Abandoned
• 1985
  • 1985-05-13 ES ES543082A patent/ES8603881A1/es not_active Expired
  • 1985-05-13 ES ES543083A patent/ES8603882A1/es not_active Expired
  • 1985-05-13 ES ES543084A patent/ES543084A0/es active Granted
  • 1985-05-13 ES ES543085A patent/ES543085A0/es active Granted
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